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By way of background, everyone has two copies of the Mef2c gene, one from your mother and one from your father. The Mef2c gene, which was discovered in my laboratory some years ago when it was at Harvard Medical School, encodes a protein, designated MEF2C, which is a transcription factor. A transcription factor is a molecule that controls the activation of many genes, and in the case of MEF2C, the genes that are controlled are important for nervous system development, as well as for the heart, the retina, and the immune system. In MEF2C Haploinsufficiency Syndrome (MHS), once copy is mutated, thus impairing its function. In the vast majority of cases (but not all), the other gene works perfectly well; however, its activity is only half of normal since once copy of the gene is not working.

Our first strategy to treat MHS was to screen for drugs that increase the activity of the remaining normal copy of the Mef2c gene in order to simulate NORMAL function of people who have two normal copies. We now have developed two compounds that work in this manner, can penetrate the brain, and can treat injured nerve cells. We are performing preclinical testing on human induced pluripotent stem cell (hiPSC)-derived nerve cells from the skin biopsies of several of your children, and also on a genetic model that we have constructed which simulates MHS in a living organism (the mouse).

Our second strategy, which has also borne some success to date, is to correct a major downstream effect of the Mef2c mutation. In this case, we do not try to treat the brain by activating or correcting MEF2C itself, but rather we treat a downstream effect of having too little MEF2C. We and others have discovered that many cases of Autism Spectrum Disorder (ASD), as well as other neurodevelopmental disabilities, result at least in part from an altered excitatory to inhibitory ratio (E/I ratio) of the normal electrical activity in the brain. Nerve cells in the brain communicate with one another via specialized endings, called synapses; synapses can be either inhibitory or excitatory, and it is important to have both to maintain electrical ‘balance’ in the brain. The synapses appear to be dysfunctional in children with MHS. This dysfunction results in an altered amount of excitatory and inhibitory synapses, causing the deranged E/I ratio. You can read more about this in an article published recently in the journal Nature Medicine by my colleague and collaborator Dan Geschwind, MD, PhD at UCLA School of Medicine here in California. In brief, Dan summarizes all the known genetic causes of ASD, including Mef2c, and presents the unifying theory that the E/I ratio is disrupted in ASD as well as in several other neurologic conditions. Our group has now synthesized a new drug that CORRECTS THE E/I RATIO in our mouse model of MHS. Dan Geschwind is a co-author on this paper, which received favorable peer review at one of the Nature companion journals, and will hopefully be published soon. We think that this drug has the greatest chance of being tested clinically in humans in the near future. Importantly, Dan Geschwind’s work also shows that MEF2 transcription factor activity is linked to other genes involved in ASD, indicating that our efforts to treat dysfunctional MEF2C activity may well treat the other forms of ASD as well.

Finally, our third approach to potentially treat MHS uses a new genetic technique called CRISPR/Cas9. This new method allows us to correct the genetic defect in the hiPS cells that were derived from the skin biopsies of some of your children. Potentially, the same technique could one day be used in a living human being. While this is a very exciting approach, it is also futuristic and probably a way off before it could be used in humans. One remaining problem, of course, is that by the time we recognize the disease in a child, much of the normal development has already occurred and probably cannot be corrected. However, we now know from our work on mouse models as well as clinical trials on other forms of ASD, that treatment of young children can reverse many of the symptoms of the disease, so there is hope for all of us.

I hope that this brief, lay introduction into how we are performing scientific experiments in order to develop treatments, and perhaps cure this syndrome one day, is helpful to you and the thousands of families like yours with MHS children and other forms of ASD. I am not only a scientist in the laboratory but also a clinician actively seeing patients with MHS and other neurologic conditions. As some of you know, I am also a father and have a child myself with a major neurodevelopmental disorder (although it is not MHS). Therefore, I feel the urgency in developing a treatment for our children, probably quite similar to your own feelings. Our scientific group is working hard on your behalf and love your children, just as you do.